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Electronic supplementary material 1 Consensus Validation of the FORTA (“Fit fOR The Aged”) List: a Clinical Tool for Increasing the Appropriateness of Pharmacotherapy in the Elderly Drugs & Aging Alexandra M. Kuhn-Thiel, MD1, Christel Weiß, PhD2, Martin Wehling, MD1, and the FORTA authors/expert panel members From the 1Institute for Experimental and Clinical Pharmacology, Department of Clinical Pharmacology, Center for Geriatric Pharmacology, Medical FacultyMannheim, University of Heidelberg; 2Department of Medical Statistics, Biomathematics and Information Processing, Medical Faculty Mannheim, University of Heidelberg e-mail: [email protected] 1 The F O R T A List “Fit for The Aged“ Expert Consensus Validation 2012 FORTA A B C D Alexandra M. Kuhn-Thiel, MD1, Christel Weiß, PhD2, Martin Wehling, MD1 1 Institute of Clinical Pharmacology, Center for Geriatric Pharmacology, Medical Faculty of the University of Heidelberg in Mannheim 2 Department of Medical Statistics, Biomathematics and Information Processing, Medical Faculty of the University of Heidelberg in Mannheim 2 Disclaimer Please note that the FORTA Concept was conceived and developed in Germany. This project, in conjunction with a clinical study aimed at implementing the FORTA List in a controlled clinical setting, is funded by a grant from the German Research Foundation (Deutsche Forschungsgesellschaft, DFG, Grant Nr. WE 1184/15-1). While building on an international foundation of medical evidence and experience for the medications listed, including already existing “negative lists” and classification systems, the FORTA List primarily reflects prescribing trends in Germany and Austria. It is our hope and aim, however, that the underlying principle, including the diagnosis-dependent, evidence-based labeling of specific substances, may ultimately be applied above and beyond national borders. The FORTA labels themselves, being evidence-based, may possibly, during the course of further consensus evaluation procedures, be subject to change, depending on the state of evidence and clinical experience for a given substance. With the aim of designing a user-friendly clinical tool, a summary of pertinent comments is provided directly in the FORTA List, drawing on the Delphi experts’ extensive clinical experience. This is however by no means comprehensive and does not necessarily refer to specific evidence or sources. Thus, the authors’ selection of recommendations, comments and warnings may be subjective. ‘No comment’ reflects the absence of noteworthy or relevant words of information or caution within the context of the expert evaluation. All information herein is believed to be true and accurate. Neither the authors nor the University of Heidelberg or affiliated institutions, as the publishers of this list, can accept legal responsibility for any errors made in the contents of this list. The FORTA Team welcomes all comments and criticism which may contribute to the quality, security and user friendliness of the FORTA List in everyday clinical practice. 3 The FORTA Concept, original authors and expert panel for the FORTA classification system Original authors of the FORTA List Martin Wehling, MD (Creator of the FORTA Concept); Institute of Clinical Pharmacology, Medical Faculty Mannheim, Heidelberg University Heinrich Burkhardt, MD; University Hospital Mannheim, Heidelberg University, Germany Lutz Frölich, MD; Central Institute of Mental Health, Mannheim, Germany Stefan Schwarz, MD; Central Institute of Mental Health, Mannheim, Germany Ulrich Wedding, MD; Division of Palliative Care, University Hospital Jena, Clinic for Internal Medicine II, Jena, Germany FORTA Expert Review Panel 2012 The following 20 individuals, representing Germany and Austria, provided their expertise for purposes of assessing and amending the FORTA List. We are very grateful for all participants’ collective, intensive efforts towards the improvement of a newly emerging field of focus; they received no honoraria in connection with this project. All panel members contributed actively to the development of the content and the presentation of the FORTA List. The result of this cooperation is thus not only the validation and endorsement of the FORTA List, but also the simultaneous streamlining of the overall FORTA Concept. 4 Expert Panel Members and their affiliations Jürgen Bauer, MD: Geriatrics Centre Oldenburg, University of Oldenburg, Rahel-Straus-Straße 10, 26133 Oldenburg, Germany Heiner K. Berthold, MD: Clinic of Internal Medicine and Geriatrics, Bielefeld Evangelical Hospital (EvKB), Schildescher Straße 99, 33611 Bielefeld, Germany Peter Dovjak, MD: Gmunden Hospital, Department of Acute Geriatric Medicine, Miller-von-Aichholz-Straße 49, A-4810 Gmunden, Austria Helmut Frohnhofen, MD: Essen-Mitte Hospital, Knappschafts Hospital, Teaching Hospital at the University of Duisburg in Essen, Am Deimelsberg 34a, 45276 Essen, Germany and Faculty of Health, University of Witten-Herdecke Thomas Frühwald, MD: Hietzing Hospital and Neurological Center Rosenhügel, Wolkersbergenstraße 1, 1130 Vienna, Austria Christoph Gisinger, MD: Haus der Barmherzigkeit, Danube University Krems, Seeböckgasse 30a, 1160 Vienna, Austria Manfred Gogol, MD: Lindenbrunn Hospital, Geriatric Department, Lindenbrunn 1, 31863 Coppenbruegge, Germany Markus Gosch, MD: Regional Hospital Hochzirl, Anna-Dengel House, 6170 Zirl, Austria Hans Gutzmann, MD: Hedwigshöhe Hospital, Clinic for Psychiatry, Psychotherapy and Psychosomatic Medicine, Höhensteig 1, 12526 Berlin, Germany Isabella Heuser, MD: Charité University Hospital Berlin, Department of Psychiatry and Psychotherapy, University Medicine Berlin, Campus Benjamin Franklin , Eschenallee 3, 14050 Berlin, Germany Werner Hofmann, MD: Friedrich Ebert Hospital, Clinic for Geriatric Medicine, Friesenstrasse 11, 24534 Neumuenster, Germany Michael Hüll, MD: Center for Geriatric Medicine and Gerontology Freiburg, University Clinic Freiburg, Lehener Straße 88, 79106 Freiburg, Germany Bernhard Iglseder, MD: Department of Geriatric Medicine, Christian-Doppler-Klinik, Paracelsus Medical University, Ignaz-Harrer-Str. 79, 5020 Salzburg, Austria Anja Kwetkat, MD: Jena University Hospital, Department of Geriatric Medicine, Bachstraße 18, 07740 Jena, Germany 5 Michael Meisel, MD: Deaconess Hospital Dessau nonprofit company (GmbH), Clinic for Internal and Geriatric Medicine, Gropiusallee 3, 06846 Dessau, Germany Wolfgang Mühlberg, MD: Clinic for Internal Medicine 4 – Geriatric Medicine, Frankfurt Höchst Hospital, Gotenstraße 6-8, 65929 Frankfurt am Main, Germany Wolfgang von Renteln-Kruse, MD: Albertinen Hospital/Albertinen House nonprofit company (GmbH), Center for Geriatric Medicine and Gerontology, Scientific Institution at the University of Hamburg, Sellhopsweg 18-22, 22459 Hamburg, Germany Regina Roller, MD: Medical University of Graz, Department of internal Medicine, Auenbruggerplatz 15, 8036 Graz, Austria Ralf-Joachim Schulz, MD: Geriatric Clinic at the St.-Marien Hospital, Kunibertkloster 11-13 50668 Köln, Germany Ulrike Sommeregger, MD: Hietzing Hospital and Neurological Center Rosenhügel, Wolkersbergenstraße 1, 1130 Vienna, Austria 6 F O R T A– Physician’s guide1,2 1. FORTA is evidence-based + real-life-oriented (factors such as compliance issues, age-dependent tolerance and frequency of relative contraindications are considered). 2. Classifications are indication (or diagnosis)-dependent: a medication can receive different FORTA classifications based on differing indications. 3. Contraindications always take precedence over the FORTA-classification (for example, even Class A medications may not be given if allergies are present). 4. FORTA is designed to be a quick and user-friendly clinical tool to aid in the pharmacotherapy of older patients. The system is not intended to take the place of individual therapeutic considerations or decisions. As with any simplified model, it does allow for exceptions. F O R T A – Classification System A-D Class A = Indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication Class B = Drugs with proven or obvious efficacy in the elderly, but limited extent of effect and/or safety concerns Class C = Drugs with questionable efficacy/safety profiles in the elderly which should be avoided or omitted in the presence of too many drugs, absence of benefits or emerging side effects; explore alternatives 7 Class D = Avoid if at all possible in the elderly, omit first and use alternative substances The F O R T A List3,4 Part 1 Delphi Expert Consensus Validation 2012 F O R T A A B C D Classification of the most frequently used long-term medications† for the pharmacotherapy of older patients by indication/diagnosis, ranked according to FORTA classification Newly proposed drugs are mentioned under the respective diagnosis and marked by *; they are listed in greater detail in the second part. († long-term defined as > 4 weeks. Please note that the distinction between acute/chronic may not always be clear-cut; exceptions are noted) 8 FORTA Class (original FORTA class in parentheses if different from consensus results) Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) A 20 0.975 1.1; 1 Angiotensin receptor antagonists Long-acting calcium antagonists, dihydropyridine type, for example amlodipine Betablockers A 20 0.975 1.1; 1 A 19 1.000 1.0; 1 B 19 1.000 2.0; 2 Diuretics B 19 0.974 1.9; 2 Note: Metoprolol is metabolized by CYP2D6: 5-10% of Caucasians are poor metabolizers Note: favorable in connection with cardiac insufficiency Alpha blockers Spironolactone C C 20 20 0.950 0.925 3.1; 3 3.1; 3 Note: frequent, clinically relevant hyponatremia Moxonidine Clonidine C D 20 20 0.950 0.950 3.1; 3 3.9; 4 Minoxidil D 20 1.000 4.0; 4 ARTERIAL HYPERTENSION Substance/Group Renin-Angiotensin system inhibitors ACE inhibitors Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode 9 Selection of pertinent comments given by participating experts during the consensus procedure Note: May be applied when hypertensive crisis is accompanied by tachycardia Calcium antagonists, verapamil type Aliskiren* Urapidil* CARDIAC INSUFFICIENCY Substance/Group Renin-angiotensin system inhibitors ACE inhibitors D FORTA Class (original FORTA class in parentheses if different from consensus results) 20 0.950 3.9; 4 Caution: Hypotension, QT-prolongation Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode Selection of pertinent comments given by participating experts during the consensus procedure Note: chronic use may cause persistent cough A 20 0.950 1.1; 1 Angiotensin receptor antagonists Betablockers (metoprolol, carvedilol, bisoprolol, nevibolol) A 20 0.950 1.1; 1 A 20 0.950 1.1; 1 Diuretics B 19 0.947 1.9; 2 Spironolactone B 20 0.925 2.2; 2 Digitalis preparations C 20 0.925 3.0; 3 10 Note: Metoprolol is metabolized by CYP2D6: 5-10% of Caucasians are poor metabolizers Note: Class B for patients >80 years Caution: orthostatic hypotension; increased risk of falls Note: With mild to moderate cardiac insufficiency and chronic progression; in cases of acute symptomatic cardiac insufficiency, there is generally no alternative Caution: hyperkalemia, especially in combination with ACE inhibitors and NSAIDs Caution: renal insufficiency Caution: increased toxicity in association with chronic renal illnesses (nausea, vomiting, arrhythmias) CORONARY HEART DISEASE AND STROKE Substance/Group Renin- angiotensin system blockers: ACE inhibitors Acetylsalicylic acid Unfractionated heparin and low molecular weight heparin Frequency-lowering betablockers Nitroglycerin spray, single use, acute as on-demand medication Clopidogrel Thrombolytics, especially rTPA (recombinant tissuetype plasminogen activator) Statins Nitrates, long-term FORTA Class (original FORTA class in parentheses if different from consensus results) Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Note: Further development of the FORTA system may lead to differentiation between these two diagnoses as well as more specific definition of acute/chronic treatment Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode A 20 0.975 1.1; 1 A 20 1.000 1.0; 1 A 18 1.000 1.0; 1 Caution: only for thrombosis prophylaxis in stroke patients, not for acute therapy of stroke per se A 20 1.000 1.0; 1 A 20 1.000 1.0; 1 Note: second –line therapy when hypertension is present Caution: less favorable in stroke patients Caution: not to be used in cases of acute stroke due to uncontrollable drops in blood pressure B A for stent 19 0.921 1.8; 2 B 17 1.000 2.0; 2 B C 20 20 0.875 0.950 2.0; 2 2.9; 3 11 Selection of pertinent comments given by participating experts during the consensus procedure Caution: only for secondary prevention, insufficient evidence for acute stroke Note: recommended as the only accepted therapy for acute stroke Caution: terminally ill patients Caution: some statins are metabolized by the CYP 3A4 system Note: in patients with peripheral microangiopathy, improvement in exercise capacity Gp IIb/IIIa antagonists (glycoprotein 2b/3a inhibitors) Ivabradin* CHRONIC THERAPY FOLLOWING MYOCARDIAL INFARCTION Substance/group Renin angiotensin system blockers ACE Inhibitors Acetylsalicylic acid (100 mg/d) Frequency-lowering beta blockers Nitroglycerine spray, single use as on-demand medication Influenza vaccination (inactivated subunit vaccines) Statins C FORTA Class (original FORTA class in parentheses if different from consensus results) 16 0.969 2.9; 3 Caution: combinations with other antihypertensive agents due to hypotension and risk of falls Note: acute therapy; especially indicated following interventions (PTCA and stents) with peripheral emboli, in spite of high risk of bleeding Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode A A 20 20 0.975 0.975 1.1; 1 1.1; 1 A 20 1.000 1.0; 1 A 20 1.000 1.0; 1 A 17 1.000 1.0; 1 A B for very old (>80 years) 20 0.900 1.2; 1 12 Selection of pertinent comments given by participating experts during the consensus procedure Note: metoprolol is metabolized by CYP2D6: 5-10% of Caucasians are poor metabolizers Clopidogrel Nitrates, long-term Fibrates Niacin Ezetimib Amiodarone All other class-I-III antiarrhythmic agents Dihydropyridine antagonists (if no hypertension) ATRIAL FIBRILLATION Substance/group Oral anticoagulation (e.g. Phenprocoumon, warfarin) Alternative: low molecular weight heparin Frequency-lowering patients B A with stent, aspirin intolerance C C C C C 19 0.974 1.9; 2 20 18 19 19 20 0.975 0.889 1.000 0.921 0.975 3.0; 3.2; 3.0; 3.2; 3.1; D 20 1.000 4.0; 4 D 20 1.000 4.0; 4 FORTA Class (original FORTA class in parentheses if different from consensus results) Note: secondary prevention 3 3 3 3 3 Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode A 20 0.975 1.1; 1 A 19 0.974 1.1; 1 A 20 1.000 1.0; 1 13 Selection of pertinent comments given by participating experts during the consensus procedure Caution: lack of evidence as to long-term use betablockers Digoxin B 20 (R1) 19 (R2) 0.800 2.4; 2 (R1) 2.4; 2 (R2) Digitoxin (D) C 20 (R1) 19 (R2) 0.525 3.1; 4 (R1) 2.5; 2 (R2) Class III antiarrhythmic agent Dronedarone Diltiazem, Verapamil (B) C C 18 (R1) 18 (R2) 20 0.555 0.975 2.9; 3 (R1) 3.0; 3 (R2) 3.1; 3 Acetylsalicylic acid (100 mg/d) Class III antiarrhythmic agent Amiodarone C 20 0.850 3.1; 3 Caution: rarely sufficient; risk of adverse effects C 19 0.868 3.1; 3 Recommendation: discontinue when atrial fibrillation persists and tachyarrhythmia can be controlled otherwise All other class I-III antiarrhythmic agents Dabigatran* Rivaroxaban* D 20 1.000 4.0; 4 CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) FORTA Class (original FORTA class in parentheses if different from consensus results) Recommendation: When possible, reduce dosage, even with normal renal function and drug monitoring level Caution: accumulation in patients with renal insufficiency; adverse effects (loss of appetite, nausea) Note: may be easier to regulate in patients with chronic kidney disease (CKD) than digoxin; fluctuations in liver function are observed less frequently than in renal function Caution: regular monitoring Caution: lack of evidence for elderly patients, risk/benefit ratio difficult to estimate; liver toxicity Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode Substance/group 14 Selection of pertinent comments given by participating experts during the consensus procedure Inhalative glucocorticoids A 20 1.000 1.0; 1 Inhalative long-acting parasympatholytic agents Systemic glucocorticoids, acute, short-term use in cases of exacerbation Antibiotics (acute) in cases of exacerbation, after calculated selection and, if necessary, according to antibiogram Long-term administration of oxygen Annual influenza immunizations Pneumococcal immunizations for persons ≥ 65 years Inhalative beta 2 mimetic agents Theophyllin A 19 1.000 1.0; 1 A 20 0.975 1.1; 1 A 20 0.975 1.1; 1 A 19 0.974 1.1; 1 A 19 1.000 1.0; 1 A 18 0.972 1.1; 1 B 19 1.000 2.0; 2 C 20 0.875 3.2; 3 Mucolytic agents, e,g, acetyl cystein, bromhexin Systemic glucocorticoids, chronic use Antitussives: opioid A., e.g. codein; non-opioid A., e.g. butamirate C 20 0.950 3.1; 3 D 20 0.975 4.0; 4 D 20 1.000 4.0; 4 FORTA Class (original Expert ratings on a numerical scale: 15 Note: therapy of asthma Caution: compliance problems, frailty syndrome Note: therapy of COPD Caution: compliance problems, frailty syndrome Caution: pCO2 ↑ Caution: side effect profile: tremor, nausea, loss of appetite, tachycardia FORTA class in parenteses if different from consensus results) A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode A 20 0.975 1.1; 1 Recommendation: calcium supplements only when sufficient calcium intake is not guaranteed A 20 0.900 1.2; 1 Note: oral less effective than intravenous application A 17 0.882 1.2; 1 Caution: possible risk of thromboembolism Teriparatide B 15 0.967 1.9; 2 Strontium ranelate B 17 (R1) 18 (R2) 0.794 2.1; 2 (R1) 2.1; 2 (R2) Note: cost issues may limit use Note: favorable evidence for patients > 80 years; daily administration, as well as strict adherence to scheduling around mealtimes Caution: contraindicated in patients with renal insufficiency Alfacalcidol Parathormone Nandrolone decanoate Fluoride Hormone replacement therapy (HRT): estrogen, except for perimenopausal) Denosumab* C C D D 18 19 18 19 0.944 0.921 1.000 1.000 2.9; 2.9; 4.0; 4.0; D 19 0.921 3.8; 4 OSTEOPOROSIS Substance/Group Calcium and Vitamin D supplements Bisphosphonates (Alendronate, Ibandronate, Risendronate, Zoledronate) Raloxifen FORTA Class (original FORTA class in parentheses 3 3 4 4 Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Consensus 16 Selection of pertinent comments given by participating experts during the consensus procedure TYPE II DIABETES MELLITUS Substance/group Insulin and insulin analogs 3rd generation sulfonylureas (for example, glimepiride) 1st generation sulfonylureas (for example, glibenclamide) Metformin Acarbose Glinides (for example, nateglinide) DPP4 (Dipeptidylpeptidase) Inhibitors GLP1 (Glucagon-Like Peptide-1) analogs PPAR-ɣ Ligands (Peroxisomal ProliferatorActivated Receptor gamma) Pioglitazone Rosiglitazone if different from consensus results) Nr. of raters coefficient, Round 1 (cutoff 0.800) Mean; Mode A A 19 20 0.974 0.925 1.1; 1 1.2; 1 B 19 0.842 2.3; 2 Caution: risk of hypoglycemia B 20 0.975 2.0; 2 B C 19 18 0.816 0.972 2.4; 2 2.9; 3 Note: lower risk of hypoglycemia Caution: contraindicated in patients with impaired renal function Note: less effective, favorable alternatives available Note: within this group, repaglinide may be most favorable in terms of controllability C 19 0.895 2.8; 3 C 19 0.974 3.1; 3 C 20 0.950 3.1; 3 D 20 1.000 4.0; 4 FORTA Class (original FORTA class in Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 17 Selection of pertinent comments given by participating experts during the consensus procedure Caution: risk of edema Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode B 20 0.900 2.0; 2 B C (C) D 19 17 19 (R1) 20 (R2) 0.895 0.853 0.763 2.1; 2 3.3; 3 3.5; 3 (R1) 3.7; 4 (R2) (C) D (C) D (C) D 20 (R1) 19 (R2) 20 (R1) 20 (R2) 19 (R1) 20 (R2) 0.750 3.5; 3.7; 3.5; 3.6; 3.5; 3.8; 3 (R1) 4 (R2) 3 (R1) 4 (R2) 3 (R1) 4 (R2) 20 (R1) 20 (R2) 18 (R1) 19 (R2) 19 (R1) 20 (R2) 0.800 Antioxidants: Vitamin E, Selenium, Vitamin C (C) D (C) D (C) D 3.4; 3.6; 3.4; 3.7; 3.6; 3.9; 3 (R1) 4 (R2) 3 (R1) 4 (R2) 4 (R1) 4 (R2) Phytotherapeutic agents, e.g. Ginseng Hormone preparations, e.g. DHEA (C) D (C) D 20 (R1) 20 (R2) 20 (R1) 20 (R2) 0.725 3.6; 3.8; 3.6; 3.9; 4 (R1) 4 (R2) 4 (R1) 4 (R2) DEMENTIA Substance/group Acetylcholinesterase inhibitors for example, Donepezil, Galantamine, Rivastigmine Memantine Statins Selegiline Nimodipine Ginkgo biloba Ergoline derivatives Piracetam Pyritinol parentheses if different from consensus results) 0.775 0.763 0.778 0.711 0.700 18 Selection of pertinent comments given by participating experts during the consensus procedure Note: treatment of dementia of the Alzheimer type Note: risk overrides any benefit Caution: contraindicated when severe cardiac and cardiovascular illnesses are present Note: lack of evidence as to benefits Note: lack of evidence as to benefits Caution: Interaction potential via CYP 450 system Note: lack of evidence as to benefits Note: no longer administered in Austria due to risk of toxic effects Note: lack of evidence as to benefits Note: lack of evidence as to benefits Note: lack of evidence as to benefits Note: vitamin deficiency due to malnutrition is common in association with dementia Note: lack of evidence as to benefits Note: lack of evidence as to benefits (Dehydroepiandrosterone), Testosterone Antiphlogistics, e.g. Indomethacin Desferrioxamine BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF DEMENTIA (BPSD) BPSD: DEPRESSION Substance/group SSRI (Selective Serotonin Reuptake Inhibitors) Citalopram/Escitalopram, Sertralin, Fluoxetin in the usual dosages Mirtazapine (15-45mg/d) SNRI (SerotoninNoradrenalin-ReuptakeInhibitors) Venlafaxin, Duloxetin D 20 1.000 4.0; 4 D 19 1.000 4.0; 4 FORTA Class (original FORTA class in parentheses if different from consensus results) Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode Selection of pertinent comments given by participating experts during the consensus procedure B 20 0.900 2.1; 2 Recommendation: maximum 20mg for citalopram Caution: risk of protracted serotonin syndrome with fluoxetin B 20 0.875 2.2; 2 Recommendation: well-tolerated in low doses (15mg) B 18 0.917 2.2; 2 19 BPSD: PARANOIA, HALLUCINATION Substance/group Risperidone (initially 0,5-1 mg/d) Haloperidol (initially 0.5 mg/d, max. 3 mg/d) Quetiapine (25-200 mg/d) Aripiprazole (2-15 mg/d) Clozapine (10-50 mg/d) BPSD: RESTLESSNESS, AGITATION, (AGGRESSIVENESS) FORTA Class (original FORTA class in parentheses if different from consensus results) Nr. of raters (D) C 20 (R1) 20 (R2) 0.500 3.0; 2 (R1) 2.7; 2 (R2) (D) C 19 (R1) 20 (R2) 0.632 3.3; 4 (R1) 3.0; 3 (R2) (D) C (D) C D 20 (R1) 20 (R2) 19 (R1) 17 (R2) 20 (R1) 19 (R2) 0.575 3.2; 2.9; 3.6; 3.4; 3.6; 3.7; FORTA Class (original FORTA class in parentheses if different from consensus results) Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Consensus coefficient, Round 1 (cutoff 0.800) 0.789 0.800 Mean; Mode 4 (R1) 3 (R2) 4 (R1) 4 (R2) 4 (R1) 4 (R2) Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Note: These drugs should be considered critically under any circumstances; they may however be indicated for the therapy of older patients for whom other forms of intervention are not possible or feasible. Based on the results of the Delphi Consensus Procedure, this indication group is under intensified observation for further development. Selection of pertinent comments given by participating experts during the consensus procedure Note: alternatives are few, also an option when aggressiveness is displayed Caution: keep dosages and treatment time at a minimum Note: only licensed substance for treatment of delirium when drug therapy is necessary; very few alternatives Caution: strict adherence to maximum dosage Note: May be an option when haloperidol is contraindicated, also in cases of Parkinson-related delirium Recommendation: treatment of Lewy Body dementia Note: These drugs should be considered critically under any circumstances; they may however be indicated for the therapy of older patients for whom other forms of intervention are not possible or feasible. Based on the results of the Delphi Consensus Procedure, this indication group is under intensified observation for further development. Mean; Mode Selection of pertinent comments given by participating experts during the consensus procedure Substance/group 20 Trazodone (50-200 mg/d) Risperidone (initially 0.5-1 mg/d, maximum 3 mg/d) Quetiapine (25-200 mg/d) Melperone (25-150 mg/d) Pipamperone (20-120 mg/d) Clomethiazole (5-15 mg/d) BPSD: SLEEP DISORDERS Substance/group Slow-release melatonin (2-4 mg) Zopiclone (3.75-7.5 mg) Tetracyclic antidepressant Mirtazapine (15-30mg) Tricyclic antidepressant Doxepine (25-50mg) C (D) C (D) C (D) C D D FORTA Class (original FORTA class in parentheses if different from consensus results) 17 20 (R1) 20 (R2) 19 (R1) 20 (R2) 20 (R1) 20 (R2) 19 (R1) 17 (R2) 19 0.912 0.625 0.763 0.675 0.789 0.947 3.2; 3 3.3; 4 (R1) 2.7; 2 (R2) 3.5; 4 (R1) 3.3; 3 (R2) 3.4; 4 (R1) 3.4; 4 (R2) 3.6; 4 (R1) 3.6; 4 (R2) 3.9; 4 Recommendation: ≤ 2mg/d Note: also effective in treating aggressiveness Note: also effective in treating aggressiveness; favorable extrapyramidal side effect profile Note: also effective in treating aggressiveness Note: also effective in treating aggressiveness Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode C 18 0.833 3.1; 3 C C 18 20 (R1) 20 (R2) 1.000 0.775 3.0; 3 3.0; 3 (R1) 3.0; 3 (R2) C 18 0.801 3.4; 3 21 Selection of pertinent comments given by participating experts during the consensus procedure Caution: not for long-term use Recommendation: lowest possible dosages recommended Recommendation: other substances should be favored when symptoms of depression are not present Caution: anticholinergic side effects FORTA Class (original FORTA class in parentheses if different from consensus results) Sertraline DEPRESSION Prophylaxis and therapy for patients with moderate to major depression Expert ratings on a numerical scale (median): A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode B 20 1.000 2.0; 2 Escitalopram B 19 1.000 2.0; 2 Citalopram B 20 0.975 2.0; 2 C 20 0.925 3.2; 3 C 20 0.825 2.7; 3 C 20 0.950 2.9; 3 C 20 0.975 3.0; 3 C 19 0.947 3.0; 3 Selection of pertinent comments given by participating experts during the consensus procedure Substance/group SSRIs (Selective Serotonin Reuptake Inhibitor) Tricyclic antidepressant Nortriptyline Tetracyclic antidepressant Mirtazapine SNRIs (SerotoninNoradrenalin Reuptake Inhibitors) Venlafaxin Duloxetin Monoamine oxidase A (MAO) inhibitor 22 Recommendation: maximum 20 mg for older patients Note: Compared to escitalopram, more marked change in QT interval due to the ineffective enantiomere Recommendation: apply lowest possible dosage Moclobemide Dopamine and norepinephrine reuptake inhibitor Bupropion Selective noradrenaline reuptake inhibitor Reboxetin Trazodone* Olanzapine* Benzodiazepines* (general, long-acting, shortacting) St. John’s Wort* C 18 0.917 3.1; 3 D 20 0.925 3.9; 4 NEW INDICATION BIPOLAR DISORDER* INSOMNIA / SLEEP DISORDERS Substance/group ω1-Benzodiazepine agonists Zolpidem Zaleplone Non-benzodiazepine hypnotic Zopiclone Butyrophenone derivative Pipamperone FORTA Class (original FORTA class if different from consensus results) Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) C 20 1.000 3.0; 3 C 18 1.000 3.0; 3 C 18 1.000 3.9; 3 C 18 0.806 3.3; 3 Mean; Mode 23 Selection of pertinent comments given by participating experts during the consensus procedure Melatonin (slow-release) Melperone* Tetracyclic antidepressant Mirtazapine Benzodiazepines, e.g. Oxazepam (medium half-life) Triazolam (very short half-life) Sigma receptor agonist Opipramole Tricyclic antidepressant Doxepine Antihistamine Diphenhydramine C 18 0.861 3.2; 3 (D) C 20 (R1) 20 (R2) 0.700 3.4; 4 (R1) 3.5; 4 (R2) D 20 0.900 3.8; 4 D 19 0.974 3.9; 4 D 19 1.000 4.0; 4 D 19 0.974 3.9; 4 D 19 1.000 4.0; 4 FORTA Class (original FORTA class in parentheses if different from consensus results) Substance/Group Paracetamol (acetaminophen) Metamizole CHRONIC PAIN Recommendation: indicated in association with additional symptoms of depression; also effective in low doses (15mg) Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode A 20 0.950 1.1; 1 Caution: previous liver damage B 20 0.950 1.0; 2 Recommendation: risk/benefit relation favorable, combination therapy and regular monitoring of blood count 24 Selection of pertinent comments given by participating experts during the consensus procedure SSRI (Selective Serotonin Reuptake Inhibitors) / SNRI (SerotoninNoradrenalin-Reuptake Inhibitor), e.g. Venlafaxin Opioids, e.g. B 18 0.833 2.3; 2 Note: consider venlafaxin only in individual cases Caution: potentially delirogenic; possible limitations in patient adherence due to adverse effects (CNS, nausea, constipation) Buprenorphine B 19 0.974 2.1; 2 Tilidine/naloxone B 20 0.975 2.0; 2 Except for Morphin C 20 0.900 2.8; 3 Antiepileptic agents Pregabalin C 20 0.950 2.9; 3 Recommendation: shown to be favorable for neuropathic pain; effective in low doses and well-tolerated Carbamazepin D 20 0.875 3.8; 4 Note: little evidence available for older patients D 19 0.895 3.8; 4 Tricyclic antidepressant Amitriptylin NSAIDs (nonsteroidal antiinflammatory drugs), e.g. Naproxen Celecoxib D 20 0.975 4.0; 4 D 20 0.950 3.9; 4 Antiepileptic agent Gabapentin* Opioids* (oxycodone, 25 Recommendation: when renal function is satisfactory and no contraindications present, exceptions may be made for musculo-skeletal pain hydromorphone) NEW INDICATION EPILEPSY* FORTA Class (original FORTA class in parentheses if different from consensus results) L-DOPA Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode B 20 0.900 1.8; 2 COMT (Catechol-OMethyltransferase) Inhibitor Entacapone MAO-B inhibitors B 19 0.947 2.1; 2 Selegiline C 20 0.950 2.9; 3 Rasagiline C 19 0.974 2.9; 3 Dopamine agonists Ropinirole C 19 0.947 3.0; 3 PARKINSON’S DISEASE Selection of pertinent comments given by participating experts during the consensus procedure Substance/group 26 Note: in available guidelines, drug of choice for patients >70 years, favorable side effect profile with regard to hallucinosis and psychosis Caution: potentially delirogenic Pramipexole Caution: potentially delirogenic C 19 0.947 3.0; 3 Glutamate antagonists Amantadine Anticholinergics Biperidene INCONTINENCE Drug therapy for urge incontinence Substance/group Trospium chloride Oxybutynin Tolterodine C 19 0.921 3.1; 3 D 20 1.000 4.0; 4 FORTA Class (original FORTA class in parentheses if different from consensus results) B C C Caution: high risk of adverse effects; potentially delirogenic; possible QT-prolongation Note: indicated for dyskinesia, parenteral therapy of akinetic crisis Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode 18 19 18 0.972 0.947 0.944 1.9; 2 3.1; 3 3.1; 3 NEW INDICATION GASTROINTESTINAL ILLNESSES/ CONCOMITANT THERAPY WITH NSAIDs* 27 Selection of pertinent comments given by participating experts during the consensus procedure Caution: intensification of dementia Caution: intensification of dementia Note: Use of the FORTA system is limited for the following indications due to the highly specialized nature and complexity of treatment options, e.g. combination therapies, as well as new advances being made which may affect the state of evidence and the FORTA ratings. Strictly speaking, some of these therapy options may not be defined as long-term treatment and thus may not adhere to the FORTA principle. In general, few studies are available pertaining to older patients. Due also to the lower number of raters, this area is under intensified observation for further development. ONCOLOGICAL DISEASES: SOLID TUMORS FORTA Class (original FORTA class in parentheses if different from consensus results) Tamoxifen Aromatase inhibitors INDICATION Substance/group Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode A 12 1.000 1.0; 1 A 11 1.000 1.0; 1 A 10 1.000 1.0; 1 BREAST CANCER Adjuvant therapy Hormone therapy, e.g. Immunotherapy / “Targeted” therapy Trastuzumab 28 Selection of pertinent comments given by participating experts during the consensus procedure Chemotherapy, e.g. CMF (Combination Cyclophosphamide, Methotrexate, 5Fluorouracil) AC/EC Regimen(Anthracyclin/ Epirubicin, Cyclophosphamide) BREAST CANCER Advanced Stage Hormone therapy, e.g. Tamoxifen, Aromatase inhibitors Immunotherapy/Targeted Therapy Trastuzumab / Lapatinib Chemotherapy, e.g. anthracyclins, taxanes VEGF (Vascular Endothelial Growth Factor) Inhibition Bevacizumab COLORECTAL CARCINOMA Adjuvant Therapy FOLFOX Regimen (Folinic acid, Fluorouracil, Oxaliplatin) B 8 1.000 2.0; 2 B 8 1.000 2.0; 2 A 10 1.000 1.0; 1 A 8 1.000 1.0; 1 B 7 0.929 1.9; 2 B 7 1.000 2.0; 2 B 7 1.000 2.0; 2 29 5-Fluorouracil based infusion regimen Capecitabine B 7 1.000 2.0; 2 B 7 1.000 2.0; 2 B 7 0.929 2.1; 2 B 7 0.929 2.1; 2 B 7 0.929 2.1; 2 B 7 0.929 2.1; 2 B 5 1.000 2.0; 2 Docetaxel A 5 1.000 1.0; 1 Vinorelbin A 5 1.000 1.0; 1 B 5 1.000 2.0; 2 COLORECTAL CARCINOMA Advanced stage Chemotherapy FOLFOX (Folinic acid, Fluorouracil, Oxaliplatin) VEGF (Vascular Endothelial Growth Factor) Inhibition Bevacizumab EGFR (Epidermal-GrowthFactor-Receptor) Inhibition Cetuximab Panitumumab BRONCHIAL CARCINOMA Adjuvant therapy Adjuvant chemotherapy (Cisplatin-based) BRONCHIAL CARCINOMA Advanced Stage Primary combination therapy Cisplatin/Gemcitabin, or Cisplatin/Vinorelbin 30 GASTRIC CANCER ECF Regime (Epirubicin, Cisplatin, 5-Fluorouracil) ONCOLOGICAL DISEASES HEMATOLOGICAL NEOPLASIAS INDICATION Substance/group MDS (Myelodysplastic syndrome) Azacytidine AML (Acute myeloid leukemia) Anthracyclines + cytosine arabinoside (cytarabine) CLL (Chronic lymphatic leukemia) Chlorambucil, Fludarabin, Bendamustin Multiple myeloma A FORTA Class (original FORTA class in parentheses if different from consensus results) 5 0.900 1.2; 1 Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) Mean; Mode A 6 1.000 1.0; 1 A 7 0.857 1.3; 1 A Expert recommendation: alternative FLO (5-fluorouracil, folinic acid, oxaliplatin); capecitabin shown to be particularly favorable, regardless of age 8 0.875 1.3; 1 Primary therapy with 31 Selection of pertinent comments given by participating experts during the consensus procedure Caution: based on a study comparing fludarabin with chlorambucil, more deaths associated with fludarabin Prednisolone Thalidomide Melphalan A 8 1.000 1.0; 1 A 8 0.875 1.3; 1 A 8 0.875 1.3; 1 FORTA Class Nr. of raters Consensus coefficient, Round 1 (cutoff 0.800) A 13 1.000 1.0; 1 A 16 1.000 1.0; 1 Caution: anticholinergic side effects for dimenhydrinate B 14 0.964 1.9; 2 Note: effective for anemia associated with renal insufficiency ONCOLOGICAL SUPPORTIVE THERAPY Substance/group G-CSF (Granulocyte Colony Stimulation Factor) Antiemetic agents (e.g. 5HT receptor inhibitors) Erythropoesis Stimulating Agents, ESA Expert ratings on a numerical scale A=1, B=2, C=3, D=4 Mean; Mode Selection of pertinent comments given by participating experts during the consensus procedure NEW INDICATION ANEMIA* *This substance or indication was suggested by the participating experts during the course of Round 1 and evaluated by the experts during Round 2, see second table below. R1= Round 1 R2= Round 2 32 The F O R T A List Part 2 Delphi Expert Consensus Validation 2012 F O R T A A B C D NEW SUBSTANCES/INDICATIONS SUGGESTED BY EXPERTS Results to be corroborated in future consensus/research projects Classification of long-term medications† for the pharmacotherapy of older patients by indication/diagnosis, ranked according to FORTA classification (†long-term defined as > 4 weeks. Please note that the distinction between acute/chronic may not always be clear-cut; exceptions are noted) Rater-based FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Nr. of raters κ-index Aliskiren C 13 0.197 2.5; 2 Urapidil C 13 1.000 3.0; 3 EXISTING INDICATION ARTERIAL HYPERTENSION Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode Selection of pertinent comments given by participating experts during the consensus procedure Substance/group 33 Expert recommendation: favorable alternative to ACE inhibitors; recommendations as to dosage are available Caution: problematic in patients with impaired hepatic and renal function EXISTING INDICATION CORONARY HEART DISEASE Substance/group Ivabradin EXISTING INDICATION ATRIAL FIBRILLATION Rater-based FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Nr. of raters κ-index C 10 0.289 Rater-based FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode 2.6, 3 Selection of pertinent comments given by participating experts during the consensus procedure Caution: numerous interactions via Cytochrome P 3A4 possible; QT prolongation Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Nr. of raters κ-index Mean; Mode Selection of pertinent comments given by participating experts during the consensus procedure Substance/group Rivaroxaban B 13 0.214 2.1; 2 Dabigatran B 13 0.111 2.2; 2 EXISTING INDICATION OSTEOPOROSIS Rater-based FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Note: net benefit compared to vitamin K antagonists demonstrated in registration trials; still insufficient clinical evidence Note: net benefit compared to vitamin K antagonists demonstrated in registration trials; still insufficient clinical evidence Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode Nr. of raters κ-index 34 Selection of pertinent comments given by participating experts during the consensus procedure Denosumab A 12 0.414 1.4; 1 Note: alternative when bisphosphonates/strontium ranelate are contraindicated Rater-based FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Nr. of raters κ-index Oxycodone B 20 0.628 2.2; 2 Note: elimination is independent of renal function, largely independent of liver function Hydromorphone B 20 0.740 2.2; 2 Antiepileptic agent Gabapentin C 17 0.294 2.5; 3 Note: elimination is independent of renal function, largely independent of liver function Recommendation: sufficient evidence for neuropathic pain; substance approved; low interaction potential Caution: observe recommended dosages in patients with impaired renal function EXISTING INDICATION CHRONIC PAIN Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode Selection of pertinent comments given by participating experts during the consensus procedure Opioids, e.g. EXISTING INDICATION DEPRESSION Rater-based FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode Nr. of raters κ-index Substance/group 35 Selection of pertinent comments given by participating experts during the consensus procedure Trazodone B 14 0.355 2.4; 2 Short-acting C 19 0.259 3.3; 3 Long-acting D 15 0.822 3.9; 4 General D 15 0.314 3.6; 4 St. John’s Wort D 13 0.795 3.9; 4 Benzodiazepines EXISTING INDICATION SLEEP DISORDERS/INSOMNIA Substance/group Melperone NEW INDICATION BIPOLAR DISORDER Rater-based FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Nr. of raters κ-index C 15 0.213 Consensusbased FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Caution: in general, do not consider for long-term therapy Caution: interaction potential via cytochrome P450 Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode 3.1; 3 Selection of pertinent comments given by participating experts during the consensus procedure Note: low anticholinergic potential Caution: not recommended for insomnia alone Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode Nr. of raters κ-index 36 Selection of pertinent comments given by participating experts during the consensus procedure Substance/group Lithium C 15 0.441 3.3; 3 Consensusbased FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Nr. of raters κ-index Substance/group Proton pump inhibitors (PPI) B 14 0.223 2.1; 2 H2 receptor antagonists C 14 0.648 3.1; 3 NEW INDICATION GASTROINTESTINAL ILLNESSES/CONCOMITANT THERAPY WITH NSAIDs NEW INDICATION ANEMIA Substance/group Substitution (iron, vitamin B12, folic acid in cases of deficiency) Erythropoetin-stimulating agents (ESA) in patients with renal insufficiency Caution: extremely narrow therapeutic margin; careful consideration of indication Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode Consensusbased FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Nr. of raters κ-index A 12 1.000 1.0; 1 A 11 0.564 1.2; 2 Selection of pertinent comments given by participating experts during the consensus procedure Caution: often freely prescribed Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Mean; Mode 37 Selection of pertinent comments given by participating experts during the consensus procedure Iron substitution in patients with cardiac insufficiency Proof of iron deficiency A 12 0.596 1.2; 1 No proof of iron deficiency B 9 0.444 2.1; 2 NEW INDICATION EPILEPSY Please note that the treatment of epilepsy, as a highly specialized area, may exceed the authority of the FORTA system. Consensusbased FORTA Class (bold if: κ > 0.500, rater number ≥ 10 and label distance < 2) Expert ratings on a numerical scale: A=1, B=2, C=3, D=4 Nr. of raters κ-index Levetiracetam B 11 0.273 1.6; 2 Lorazepam B 9 0.148 1.8; 2 Lamotrigin B 12 0.273 1.5; 1 Valproic acid B 12 0.596 2.2; 2 Midazolam B 9 0.481 2.2; 2 Mean; Mode Selection of pertinent comments given by participating experts during the consensus procedure Substance/group 38 Expert recommendation: for focal and generalized epilepsy as well as status epilepticus Caution: previous psychiatric illnesses, particularly depression Expert recommendation: favored (intravenous application) for status epilepticus, fewest respiratory depressive effects present; most favorable lasting anticonvulsive effects Caution: arterial hypotension Caution: risk of exanthema Caution: potential adverse effects; potential interactions; risk of encephalopathy Note: buccal application also possible for status epilepticus Gabapentin B 12 0.293 1.6; 2 Pregabalin B 11 0.321 1.6; 2 Topirimate B 9 0.481 2.2; 2 Carbamazepin C 12 0.212 2.5; 2 Phenytoin D 10 0.733 3.9; 4 Oxcarbazepine D 10 0.526 3.6; 4 Diazepam D 8 0.429 3.8, 4 39 Caution: potentially high respiratory depressive effects: monitoring required for use Caution: monitor renal function Expert recommendation: only focal epilepsy; monitor renal function; advantageous with additional anxiety disorders or neuropathic pain syndromes are present Caution: Numerous interaction, for example with antidiabetics; risperidone; HCT; caution with impaired renal function; should be left to experts in the field Caution: potential risk of hyponatremia Caution: only as reserve preparation (intravenous) for status epilepticus Caution: high rate of hyponatremia Caution: potential respiratory depressive effects; only short anticonvulsive effects Note: rectal application possible for status epilepticus REFERENCES 1. Wehling M. Drug therapy in the elderly: too much or too little, what to do? A new assessment system: fit for the aged FORTA. Dtsch Med Wochenschr 2008;133:2289-91. Epub 2008 Oct 22. 2. Wehling M. Multimorbidity and polypharmacy: how to reduce the harmful drug load and yet add needed drugs in the elderly? Proposal of a new drug classification: fit for the aged. J Am Geriatr Soc 2009;57:560-561. 3. Wehling M, Burkhardt H. Arzneitherapie für Ältere. Springer-Verlag, Heidelberg, 2. Auflage 2011. 4. Wehling M, Ed., Drug Therapy for the Elderly. Springer-Verlag, Wien 2013 40 SUMMARY OF STATISTICAL METHODS Consensus Coefficient Consensus parameters were generated by calculating the percentage of experts’ FORTA ratings (minus abstentions) agreeing with the original FORTA values, both overall and for each item separately (n = 190). The coefficients were then corrected (cons_corr) to weight the degree of deviation between the experts’ individual FORTA ratings, expressed in terms of range class, from 0-3 as defined: Range = 0: unanimity among all experts (no deviation); Range = 1: greatest range only from A to B or B to C, or C to D (neighboring classes), ½ weight; Range = 2: greatest distance from A to C or B to D, 2/3 weight; Range = 3: greatest distance from A to D, full weight. Frequency of substances in defined range groups according to degree of consensus Range 0 1 2 3 Frequency (n total=190) Percent 54 86 43 7 28.42 45.26 22.63 3.68 Cons_corr coefficients ranged from 0.500 to 1.000 (mean 0.922, median 0.950). Substances falling short of our established cons_corr cutoff of 0.800 underwent re-evaluation in a second round: n=24 41 FORTA List Part 1 Confirmation/determination of FORTA labels In order to compare the rater-based FORTA labels with the original author-based labels, the labels A, B, C and D were transformed as follows: A→ 1 B→2 C→3 D→4 These numerical “grades” were used for the calculation of arithmetic mean. The mode (=grade appearing most frequently for rated item) is also shown. For the 24 re-evaluated items, grading was performed twice. The rater-based FORTA labels are derived from the arithmetic mean from Round 1, or if re-evaluated, from Round 2. The range for each grade was set at: If 1 ≤ m < 1.5 → FORTA Class A If 1.5 ≤ m < 2.5 → FORTA Class B If 2.5 ≤ m < 3.5 → FORTA Class C If m ≥ 3.5 → FORTA Class D m= arithmetic mean based on the grades 1-4 The results of The Delphi Consensus Validation Procedure confirmed the original FORTA labels for 90% of all substances (n=190); for 19/190 substances (10%), the FORTA labels changed over the course of two rounds. All consensus-based FORTA ratings are listed in bold print: A B C D, and the original author-based FORTA ratings are supplied in parentheses: (A) (B) (C) (D). These results constitute the FORTA List Part 1. 42 FORTA List Part 2 Asterisks in the first table mark substances or indications suggested by the participating experts during the course of Round 1 and evaluated by the experts during Round 2. Selection process for new substances and indications A total of 35 substances were accepted for potential addition to the revised FORTA List. Due to the large number of substances suggested, a selection procedure was adopted: 1) acceptance of all substances suggested by ≥ 2 experts during Round 1, and all suggested indication areas; 2) acceptance of all substances/indication areas affirmed by >50% of experts during Round 2 that the substance/indication should be included in the FORTA List; 3) acceptance of all substances assigned a FORTA label by ≥ 8 raters (excluding abstentions) during Round 2. The 35 substances included o 16 new substances belonging to pre-existing FORTA indications and o 19 new substances belonging to 4 new indication groups suggested by experts A kappa index was generated for each of those added substances to analyze the distribution of the raters’ FORTA labels given. The kappa index is defined as the (proportion of “matching” labels – 0.25) / 0.75. This gives due consideration to the fact that a figure of 25% can theoretically be attained by chance alone with this particular constellation (the choice of 4 distinct labels, as with multiple choice). Mean and mode were calculated according to the numerical scale used for the original FORTA substances A→1 B→2 C→3 D→4 43 If 1 ≤ m < 1.5 → FORTA Class A If 1.5 ≤ m < 2.5 → FORTA Class B If 2.5 ≤ m < 3.5 → FORTA Class C If m ≥ 3.5 → FORTA Class D m= arithmetic mean based on the grades 1-4 In the second table, the FORTA class for substances fulfilling the following requirements is listed in bold print: kappa index > 0.500; rater number ≥ 10 giving a rating A-D (excluding abstentions) and the distance between two raters’ labels not greater than two levels (for example, A to B or B to C is tolerated, but not A to C or B to D). The FORTA classes for substances not fulfilling these requirements are listed in plain print. These results constitute the FORTA List Part 2. 44